Development of a low-dose anti-resorptive drug regimen reveals synergistic suppression of bone formation when coupled with disuse

Lloyd, Shane; Travis, Neil D.; Lu, Taihe; Bateman, Ted A.

doi:10.1152/japplphysiol.00632.2007

Cited by 18 publications

(10 citation statements)

References 37 publications

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“…Unloaded, nonirradiated mice had 74% and 60% lower trabecular bone volume fraction than normally loaded, nonirradiated mice in the tibia and femur, respectively, which is consistent with our previous experience with this model [36]. Given the approximate 1% loss of bone mass per month documented in astronauts on the ISS [1], it is not likely that astronauts will encounter this degree of bone loss on a long-duration mission; furthermore, the degree of bone loss made it more difficult to measure further changes in certain bone parameters with the addition of irradiation.…”

Section: Discussionsupporting

confidence: 91%

Effect of proton irradiation followed by hindlimb unloading on bone in mature mice: A model of long-duration spaceflight

Lloyd

Bandstra

Willey

et al. 2012

Bone

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Bone loss associated with microgravity unloading is well documented; however, the effects of spaceflight-relevant types and doses of radiation on the skeletal system are not well defined. In addition, the combined effect of unloading and radiation has not received much attention. In the present study, we investigated the effect of proton irradiation followed by mechanical unloading via hindlimb suspension (HLS) in mice. Sixteen-week-old female C57BL/6 mice were either exposed to 1 Gy of protons or a sham irradiation procedure (n=30/group). One day later, half of the mice in each group were subjected to four weeks of HLS or normal loading conditions. Radiation treatment alone (IRR) resulted in approximately 20% loss of trabecular bone volume fraction (BV/TV) in the tibia and femur, with no effect in the cortical bone compartment. Conversely, unloading induced substantially greater loss of both trabecular bone (60–70% loss of BV/TV) and cortical bone (approximately 20% loss of cortical bone volume) in both the tibia and femur, with corresponding decreases in cortical bone strength. Histological analyses and serum chemistry data demonstrated increased levels of osteoclast-mediated bone resorption in unloaded mice, but not IRR. HLS+IRR mice generally experienced greater loss of trabecular bone volume fraction, connectivity density, and trabecular number than either unloading or irradiation alone. Although the duration of unloading may have masked certain effects, the skeletal response to irradiation and unloading appears to be additive for certain parameters. Appropriate modeling of the environmental challenges of long duration spaceflight will allow for a better understanding of the underlying mechanisms mediating spaceflight-associated bone loss and for the development of effective countermeasures.

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Section: Discussionsupporting

confidence: 91%

Effect of proton irradiation followed by hindlimb unloading on bone in mature mice: A model of long-duration spaceflight

Lloyd

Bandstra

Willey

et al. 2012

Bone

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“…Excessive antiresorptive treatment and severe inhibition of bone resorption may not be necessary to protect an astronaut's skeletal system from the temporary stress of the space environment. Previous studies by our laboratory have looked at the use of more conventional bisphosphonate antiresorptives compared to OPG-Fc [21]. Over the course of a series of iterative, proof-of-concept studies we were able to demonstrate profound inhibition of bone formation at so-called supramaximal doses.…”

Section: Discussionmentioning

confidence: 97%

“…RANKL binds to its receptor RANK on the surface of osteoclasts, which leads to osteoclast activation, differentiation, and induction of bone resorption [17][18][19][20]. OPG-Fc has been shown to prevent loss of bone mass and strength in ground-based models of disuse [21], but spaceflight has the potential to have negative impacts on bone beyond those directly related to skeletal unloading. Before contemplating the use of RANKL inhibitors in astronauts, it could be important to determine whether RANKL inhibition can mitigate bone loss resulting from the panoply of factors, including microgravity, that are present in the unique setting of spaceflight.…”

Section: Introductionmentioning

confidence: 99%

Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice

Lloyd

Morony

Ferguson

et al. 2015

Bone

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Bone loss associated with microgravity exposure poses a significant barrier to long-duration spaceflight. Osteoprotegerin-Fc (OPG-Fc) is a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor that causes sustained inhibition of bone resorption after a single subcutaneous injection. We tested the ability of OPG-Fc to preserve bone mass during 12 days of spaceflight (SF). 64-day-old female C57BL/6J mice (n=12/group) were injected subcutaneously with OPG-Fc (20mg/kg) or an inert vehicle (VEH), 24h prior to launch. Ground control (GC) mice (VEH or OPG-Fc) were maintained under environmental conditions that mimicked those in the space shuttle middeck. Age-matched baseline (BL) controls were sacrificed at launch. GC/VEH, but not SF/VEH mice, gained tibia BMD and trabecular volume fraction (BV/TV) during the mission (P<0.05 vs. BL). SF/VEH mice had lower BV/TV vs. GC/VEH mice, while SF/OPG-Fc mice had greater BV/TV than SF/VEH or GC/VEH. SF reduced femur elastic and maximum strength in VEH mice, with OPG-Fc increasing elastic strength in SF mice. Serum TRAP5b was elevated in SF/VEH mice vs. GC/VEH mice. Conversely, SF/OPG-Fc mice had lower TRAP5b levels, suggesting that OPG-Fc preserved bone during spaceflight via inhibition of osteoclast-mediated bone resorption. Decreased bone formation also contributed to the observed osteopenia, based on the reduced femur periosteal bone formation rate and serum osteocalcin level. Overall, these observations suggest that the beneficial effects of OPG-Fc during SF are primarily due to dramatic and sustained suppression of bone resorption. In growing mice, this effect appears to compensate for the SF-related inhibition of bone formation, while preventing any SF-related increase in bone resorption. We have demonstrated that the young mouse is an appropriate new model for SF-induced osteopenia, and that a single pre-flight treatment with OPG-Fc can effectively prevent the deleterious effects of SF on mouse bone.

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“…Recently, Lloyd et al [58] have showed that the use of a low-dose bisphosphonate, Zolendronic acid in conjunction with Osteoprotegerin prevents bone loss occurring in mice due to 28 days of hindlimb unloading. A study by Bikle et al administered Alendronate alone to suppress unloading-induced bone loss in rats which targets resorption [35].…”

Section: Discussionmentioning

confidence: 99%

Modeled microgravity and hindlimb unloading sensitize osteoclast precursors to RANKL-mediated osteoclastogenesis

et al. 2010

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Mechanical forces are essential to maintain skeletal integrity, and microgravity exposure leads to bone loss. The underlying molecular mechanisms leading to the changes in osteoblasts and osteoclast differentiation and function remain be to fully elucidated. Due to the infrequency of spaceflights and payload constraints, establishing in vitro and in vivo systems that mimic microgravity conditions becomes necessary. We have established a simulated microgravity (modeled microgravity, MMG) system to study the changes induced in osteoclast precursors. We observed that MMG, on its own was unable to induce osteoclastogenesis of osteoclast precursors, however, 24h of MMG activates osteoclastogenesis-related signaling molecules ERK, p38, PLCγ2, and NFATc1. RANKL (and/or M-CSF) stimulation for 3-4 days in gravity of cells that had been exposed to MMG for 24h, enhanced the formation of very large TRAP positive multinucleated (>30 nuclei) osteoclasts accompanied by an upregulation of osteoclast marker genes- TRAP and cathepsin K. To validate the in vitro system, we established the hindlimb unloading system using BALB/c mice and observed a decrease in BMD of femurs and a loss of 3D microstructure of both cortical and trabecular bone as determined by microCT. There was a marked stimulation of osteoclastogenesis as determined by the total number of TRAP positive multinucleated osteoclasts formed and also an increase in RANKL stimulated osteoclastogenesis from precursors removed from the tibias of mice after 28 days of hindlimb unloading. Contrary to earlier reported findings, we did not observe any histomorphometrical changes in the bone formation parameters. Thus, the above observations indicate that microgravity sensitizes osteoclast precursors for increased differentiation. The in vitro model system described here is potentially a valid system for testing drugs for preventing microgravity induced bone loss by targeting the molecular events occurring in microgravity-induced enhanced osteoclastogenesis.

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Development of a low-dose anti-resorptive drug regimen reveals synergistic suppression of bone formation when coupled with disuse

Cited by 18 publications

References 37 publications

Effect of proton irradiation followed by hindlimb unloading on bone in mature mice: A model of long-duration spaceflight

Effect of proton irradiation followed by hindlimb unloading on bone in mature mice: A model of long-duration spaceflight

Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice

Modeled microgravity and hindlimb unloading sensitize osteoclast precursors to RANKL-mediated osteoclastogenesis

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